ANTICOAGULANT, THROMBOLYTIC, and ANTI-PLATELET DRUGS

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1 Page 1 of 21 ANTICOAGULANT, THROMBOLYTIC, and ANTI-PLATELET DRUGS Katzung (9 th ed.) Chapter 34 **** THIS VERSION HAS BEEN CHANGED COMPARED TO THE ONE MADE AVAILABLE ON WEDNESDAY APRIL 26 (sorry!) **** CRITICAL FACTS (if med school is a Minnesota forest with millions of trees, these are the red pines) 1. These drugs are used to treat strokes, myocardial infarctions, pulmonary embolisms, disseminated intravascular coagulation (DIC) and deep vein thrombosis (DVT) --- all potentially life-threatening conditions. 2. The effectiveness of thrombolytics ( clot busters ) is inversely related to the time elapsed since the thrombic crisis began these drugs are most effective within 6 hours of onset of symptoms. 3. The major classes of anticoagulant drugs have distinctly different mechanisms of action, routes of administration and adverse effects. The mechanisms of action include: activation of anticlotting factors (especially antithrombin III), direct inhibition of thrombin, inhibition of synthesis of blood coagulation factor precursors (zymogens), and activation of protein C. 4. A unique side effect to the use of HEPARIN is a transient thrombocytopenia (HIT) that occurs in 25% of patients. 5. The approved use of direct thrombin inhibitors (DTIs) is for the treatment of heparin-induced thrombocytopenia (HIT). 6. WARFARIN: has a NARROW THERAPEUTIC INDEX is NEARLY COMPLETELY (99%) BOUND TO PLASMA ALBUMIN is ELIMINATED BY HEPATIC METABOLISM (cytp450) WARFARIN IS THE PROTOTYPE FOR DRUG-DRUG INTERACTIONS! 7. DROTRECOGIN ALFA is approved for use in disseminated intravascular coagulation or DIC (fatal complication of septic shock). The use of activated protein C as a drug occurred as a result of a change in our understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation.

2 Page 2 of 21 DRUGS YOU NEED TO KNOW: ANTICOAGULANTS ARGATROBAN BIVALIRUDIN (Angiomax) DALTEPARIN (Fragmin) DROTRECOGIN ALFA (ACTIVATED PROTEIN C) (Xigris) ENOXAPARIN (Lovenox) FONDAPARINUX HEPARIN (Calciparine, Hepathrom, Lipo-Hepin, Liquaemin, Panheprin) HIRUDIN (Desirudin) 4-HYDROXYCOUMARIN (Coumadin) LEPIRUDIN (Refludan) WARFARIN (Athrombin-K, Panwarfin) XIMELAGATRAN (Exanta) ANTIDOTES PHYTONADIONE (Vitamin K 1 ) PROTAMINE SULFATE AMINOCAPROIC ACID (EACA) (generic, Amicar) (in bleeding disorders handout!) THROMBOLYTICS ANISTREPLASE (APSAC; Eminase) STREPTOKINASE (Streptase, Kabikinase) TISSUE PLASMINOGEN ACTIVATORS (tpas): ALTEPLASE (Activase), RETEPLASE (Retavase), TENECTEPLASE (TNKase) UROKINASE (Abbokinase) ANTIPLATELET DRUGS ABCIXIMAB (Centocor) ACETYLSALICYLIC ACID (Aspirin) CLOPIDOGREL (Plavix) DIPYRIDAMOLE (Persantine) EPTIFIBATIDE (Integrilin) TICLOPIDINE (Ticlid) TIROFIBAN (Aggrastat) IMPORTANT MATERIAL FROM OTHER LECTURES: 1. Principles of pharmacokinetics and pharmacodynamics, esp. therapeutic index, drug metabolism, the cytochrome P450 system (Dr. Knych, Principles), and types of biological variability (Dr. Eisenberg, Principles). 2. Coagulation and thrombosis (Drs. Krafts and Prohaska, Hematopoiesis). OBJECTIVES: 1. Be able to diagram the coagulation and fibrinolytic pathways and the interaction of protein C with those pathways. Define how different classes of anticoagulant and fibrinolytic drugs interact with specific clotting factors and naturally occurring anticoagulants in the context of these pathways. 2. Be able to describe the biochemical mechanisms of action, therapeutic uses, contraindications and adverse effects of the specific anticoagulant and fibrinolytic agents listed above. Know the properties of agents that can reverse the actions of heparin and the oral anticoagulants.

3 Page 3 of Describe the empirical rationale for thrombolytic therapy, its limitations and the agents that are currently approved for this purpose. Be able to identify both the common and the distinguishing characteristics of thrombolytic agents. 4. Compare and contrast: a. heparin and low molecular weight heparins b. heparin and warfarin with respect to mechanism of action, administration, time to onset of activity, method of monitoring, antidotes and use during pregnancy. 5. Understand why particular disease states and co-administration of other drugs can alter the efficacy and side effects of warfarin. Be able to describe specific pharmacokinetic and pharmacodynamic principles governing the interactions of warfarin with specific drugs listed in the main section of the handout. Be able to use cytochrome P450 interaction tables to identify the interactions of other drugs with both R- and S-warfarin. 6. Know the specifics of the anti-coagulant, fibrinolytic and anti-inflammatory actions of drotrecogin alfa. THERAPEUTIC STRATEGIES These drugs are used to treat strokes, myocardial infarctions, pulmonary embolisms, disseminated intravascular coagulation (DIC) and deep vein thrombosis (DVT) --- all potentially life-threatening conditions. Degrade fibrinogen/fibrin (fibrinolytic agents) GOAL: eliminate formed clots Inhibit clotting mechanism (anticoagulants) GOAL: prevent progression of thrombosis Interfere either with platelet adhesion and/or aggregation (antiplatelet drugs) GOAL: prevent initial clot formation

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5 Page 5 of 21 THROMBOLYTIC DRUGS tpas: ALTEPLASE, RETEPLASE, TENECTEPLASE, ANISTREPLASE, STREPTOKINASE, UROKINASE Common Features The effectiveness of thrombolytics is dissolve existing lifethreatening thrombi these drugs are most effective within inversely related to the time elapsed since the thrombic crisis began 6 hours of onset of symptoms activate plasminogen to plasmin hydrolysis of fibrin and several other coagulation factors plasmin formed inside a thrombus is protected from plasma antiplasmins short activation times, and short half-lives recommended for patients with: o o o o recent acute MI (selection of patients is critical!!! Some can be harmed) extensive pulmonary emboli severe deep vein thrombosis thromboembolic stroke (tpas only) Common Contraindications/Precautions cause BLEEDING (particularly hemorrhagic stroke) can be antagonized by AMINOCAPROIC ACID (for tpas) or APROTININ (for STREPTOKINASE) o inhibitory control system can be overwhelmed producing a systemic lytic state not for use in: 1. recent surgery (10 days) 2. GI bleeding (3 months) 3. active bleeding or hemorrhagic disorder 4. previous cerebrovascular accident or active intracranial process 5. history of hypertension (diastolic > 110 mmhg) 6. pregnancy 7. aortic dissection 8. acute pericarditis thrombolytic therapy is expensive (particularly tpas)

6 Page 6 of ANISTREPLASE, STREPTOKINASE Mechanism of Action binds to and induces a conformational change in plasminogen resulting in exposure of the active site and conversion to plasmin (STREPTOKINASE itself is not intrinsically active) ANISTREPLASE is an inactive complex of STREPTOKINASE and human lys-plasminogen - more convenient (shorter infusion time) but far more expensive with an increased tendency for systemic thrombolysis Adverse Effects may evoke allergic hypersensitivity reactions, fever and anaphylaxis 2. UROKINASE Mechanism of Action kidney enzyme that directly converts plasminogen to active plasmin primarily indicated only for patients allergic to STREPTOKINASE Adverse Effects febrile episodes are common but infusion reactions and hypersensitivity (anaphylaxis) are rare 3. TISSUE PLASMINOGEN ACTIVATORS (tpas): ALTEPLASE, RETEPLASE, TENECTEPLASE genetically engineered from human melanoma cells o o ALTEPLASE is unmodified human tpa RETEPLASE has several amino acid sequences deleted o TENECTEPLASE is a recombinant version of human tpa with 3 amino acid substitutions

7 Page 7 of 21 Mechanism of Action causes selective activation of fibrin-bound plasminogen poor plasminogen activator in the absence of fibrin, i.e., theoretically confines fibrinolysis to the formed thrombus and decreases systemic activation ANTICOAGULANT DRUGS The major classes of anticoagulant drugs have distinctly different mechanisms of action, routes of administration and adverse effects.

8 Page 8 of 21 Mechanisms of Action: 1. Activation of anticlotting factors (especially antithrombin III) e.g. HEPARIN 2. Direct inhibition of thrombin e.g. HIRUDIN 3. Inhibition of synthesis of blood coagulation factor precursors (zymogens) e.g. WARFARIN 4. Activated Protein C i.e., DROTRECOGIN ALFA 1. DRUGS THAT ACTIVATE ANTICLOTTING FACTORS: HEPARIN, DALTEPARIN, ENOXAPARIN, FONDAPARINUX Generalities HEPARIN most commonly given anticoagulant for short term use (>12 million patients/year) is a complex mixture of mucopolysaccharides isolated from bovine lung or porcine intestine normally found in mast cells - unknown physiologic role strongly acidic DALTEPARIN, ENOXAPARIN low MW fragments of HEPARIN Fondaparinux synthetic formulation of the key pentasaccharide that appears to be the active component in all heparins Mechanisms of Action 1. Bind to antithrombin III, a protease inhibitor that complexes with activated clotting factors II, IX, X and XI (i.e., heparins are INDIRECT thrombin inhibitors) conformational change in ATIII exposure of ATIII active site more rapid formation of ATIII-protease complexes

9 Page 9 of 21 release of HEPARIN; activated clotting factors remain bound to ATIII 2. Coat blood vessel wall (prevents platelet binding or causes permeabilization?) Pharmacokinetics activity is standardized by bioassay must be given IV (not active orally; IM administration causes hematomas) rapid effect (within minutes); instantaneously in vitro metabolized in liver; excreted in urine HEPARIN dose is adjusted to double partial thromboplastin time (monitored by aptt) DALTEPARIN, ENOXAPARIN Greater than heparin Anti-factor Xa activity Bioavailability (SC administration) Half-life (decreased dosing) More predictable pharmacology (less need for monitoring) Less than heparin Inactivation of thrombin (IIa) Platelet inhibition Vascular permeabilization Plasma protein binding Therapeutic Indications for an immediate hypothrombic response: o massive deep-vein thrombosis o pulmonary infarct o post-operative acute MI (except brain, spinal cord or eye) o prior to cardioversion of atrial fibrillation effective anticoagulant in vitro Adverse Effects HEMORRHAGE (esp. hemorrhagic stroke) hypersensitivity

10 Page 10 of 21 transient HIT occurs in about 25% of the patients during first 5 days of treatment severe HIT A unique side effect to the use of heparin is a transient thrombocytopenia (HIT). occurs in 5% of patients o small % of patients develop antibody-mediated thrombocytopenia that is associated with thrombosis (paradoxical) o in those patients, HEPARIN should be discontinued, and treatment initiated with HIRUDIN or LEPIRUDIN, but not WARFARIN (may exacerbate the prothrombotic state) prolonged administration of high doses may cause o osteoporosis o progressive reduction in antithrombin III decreased effectiveness, increased clotting o mineralocorticoid deficiency PROTAMINE SULFATE highly basic peptide that combines with HEPARIN as an ion pair lasts about 2 hours routinely used following cardiac surgery and other vascular procedures excess protamine also has an anticoagulant effect, since it can interact with platelets, fibrinogen and other plasma proteins anaphylactic reactions can occur - approximately 1% of patients with diabetes mellitus who have received protamine-containing insulin experience anaphylaxis cannot reverse many LMWH!

11 Page 11 of DIRECT THROMBIN INHIBITORS (DTIs): ARGATROBAN, BIVALIRUDIN, HIRUDIN, LEPIRUDIN, XIMELAGATRAN Mechanism of Action The approved use of DTIs is for the treatment of heparininduced thrombocytopenia (HIT). HIRUDIN was originally isolated from leech; LEPIRUDIN is the recombinant form; BIVALIRUDIN is a synthetic analogue work by 1) inhibiting fibrin binding to thrombin and 2) interacting with the thrombin active site inhibiting thrombin activity even in the presence of bound fibrin ARGATROBAN is a synthetic derivative of L-arginine - ARGATROBAN and XIMELAGATRAN bind reversibly to the thrombin active site advantages over HEPARIN: 1. inhibition of coagulation via a single mechanism of action 2. actions are independent of antithrombin III, which means they can reach and inactivate fibrin-bound thrombin inside clots 3. little effect on platelets or bleeding time 4. elimination of HIT as a side effect of treatment 5. not inactivated by platelet or plasma proteins 6. more uniform potency and increased safety 7. rebound coagulation after discontinuation of the drug is less likely with direct thrombin inhibitors Pharmacokinetics given IV (note: XIMELAGATRAN is first oral agent in this class promoted as a replacement for both WARFARIN and HEPARIN because of its immediate anticoagulant action metabolized by hydrolysis in liver, excreted in urine

12 Page 12 of 21 monitored by aptt ARGATROBAN causes elevated INRs because of test interference, making the transition to warfarin difficult Adverse Effects HEMORRHAGE: dose related; increased in patients with renal insufficiency, liver injury, or recent trauma and/or treatment with other anticoagulants 3. DRUGS THAT INHIBIT SYNTHESIS OF COAGULATION FACTOR PRECURSORS: 4-HYDROXYCOUMARIN, WARFARIN Mechanism of Action inhibit epoxide hydrase interfere with the synthesis of vitamin K and thus inhibits activation of vitamin K-dependent clotting factors (II, VII, IX, X) also decreases the activity of protein C (activated by thrombin) responsible for some side effects Pharmacokinetics WARFARIN: has a NARROW THERAPEUTIC INDEX is NEARLY COMPLETELY (99%) BOUND TO PLASMA ALBUMIN is ELIMINATED BY HEPATIC METABOLISM (cytp450) WARFARIN IS THE PROTOTYPE FOR DRUG-DRUG INTERACTIONS! rapid, complete absorption from GI; peak plasma drug concentration in < 1 hr WARFARIN is a racemic mixture of R- and S-forms S is the active enantiomer S- and R- WARFARIN are metabolized differently; S is metabolized primarily by CYP2C9, and R by CYP1A2, CYP2C19 and CYP3A4 several genes play a role in WARFARIN metabolism:

13 Page 13 of 21 polymorphisms in CYP2C9 cause about 30% of patients to be slow metabolizers (causes serum concentrations) polymorphisms in the vitamin K epoxide reductase multiprotein complex (VKOR) can confer resistance ( serum concentrations) recent clinical studies show that testing for CYP2C9 polymorphisms allows physicians to better predict the appropriate starting dose for WARFARIN, allowing the achievement of stable blood levels more quickly than the current method of trialand-error dosing defects in the coagulation cascade can also confer resistance to WARFARIN: the most common are: APC resistance (factor V Leiden), protein S deficiency, protein C deficiency, antithrombin III deficiency no in vitro effect readily crosses placenta delayed hypothrombic effect (1-3 days); t ½ 35 hr, biological t ½ 6-6O hrs small daily doses adjustment of prothrombin time takes ~ 1 week Therapeutic Indications rodenticides

14 Page 14 of 21 long-term oral treatment of deep-vein thrombosis for 2-6 months following myocardial infarction atrial fibrillation Adverse Effects HEMORRHAGE flatulence and diarrhea are common decreased protein C causes cutaneous necrosis caused during first weeks of treatment; rarely can progress to infarction (venous thrombosis) in fatty tissues, intestine and extremities bone defects (chondrodysplasia punctata) and hemorrhagic disorders in infants born to mothers taking the drug during first trimester of pregnancy ABSOLUTELY CONTRAINDICATED IN PREGNANCY

15 Page 15 of 21 DISEASE STATE and DRUG INTERACTIONS PHARMACOKINETIC ABSORPTION binding in intestine DISTRIBUTION plasma protein binding ELIMINATION cytp450 inhibition cytp450 induction PHARMACODYNAMIC SYNERGISM platelet/clotting factor function ANTAGONISM concentration of clotting factors ALTERED VITAMIN K availability of vitamin K

16 Page 16 of 21 Drug Interactions Importance of Cytochrome P450 Isozymes

17 Page 17 of 21 ILLUSTRATIVE CASE A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking METOPROLOL and WARFARIN for atrial fibrillation and AMITRIPTYLINE for diabetic neuropathy for several years. On the death of her husband, she presented with symptoms of depression and PAROXETINE was added to her medication regimen. Three days after the initiation of paroxetine therapy, the woman was brought to the emergency department by her daughter, who had found her asleep at 11 am. On awakening, the patient complained of dry mouth and dizziness. The ER physician, noting that paroxetine had been added recently, changed the patient to FLUVOXAMINE, which he thought would be less sedating. Three days later, the patient was still very sedated and dizzy, and complained of difficulty urinating. She was again brought to the ER, where bladder catheterization yielded two liters of dark urine. Her INR was 4.0. Classic cytochrome P450 interactions alcohol, barbiturates, cimetidine, fluvoxamine, phenytoin Drugs that ALWAYS Interact with Warfarin aspirin, cimetidine, phenytoin Drugs that are LIKELY to be co-administered with Warfarin (due to co-morbidity, high prescription rate and/or OTC status) By class: other anticoagulants, antiplatelet drugs, analgesics and NSAIDS, sedative-hypnotics, anti-arrhythmics, antibiotics/antifungals, antihyperlipidemics, GI drugs (esp. antacids), uricosurics (anti-gout), diuretics, thyroid medications Specifically: abciximab, alcohol (acute and chronic), allopurinol, aspirin, carbamazepine, cephalosporins, cholestyramine, cimetidine, ciprofloxacin, clofibrate, erythromycin, fluconazole, gemfibrozil, HEPARIN, HIRUDIN, lovastatin, metronidazole, miconzaole, NSAIDS, phenytoin, phytonadione, sulfonamides,

18 Page 18 of 21 thyroid hormones, trimethoprim-sulfamethoxazole Many herbal supplements: black cohosh, chamomile, dong quai, feverfew, garlic, ginger, gingko biloba, ginseng (only one that decreases efficacy) Pharmacokinetic INCREASES in Effect Inhibition of metabolism Decreased Plasma Protein Binding Acute alcohol Clofibrate Allopurinol Gemfibrozil Cimetidine Phenytoin (initially) Ciprofloxacin Sulfonamides Erythromicin Trimethoprim-sulfamethoxazole Fluconazole Lovastatin Metronidazole Sulfonamides Trimethoprim-sulfamethoxazole Pharmacokinetic DECREASES in Effect Enzyme Induction Carbamazepine Chronic alcohol Phenytoin (ultimately) Decreased absorption Cholestyramine Pharmacodynamic INCREASES in Effect Decreased platelet/ clotting factor function Abciximab ASA Heparin, Dalteparin, Enoxaparin Hirudin, Lepirudin Decreased availability of vitamin K Cephalosporins Pharmacodynamic DECREASES in Effect Increased concentrations of clotting factors Diuretics Vitamin K

19 Page 19 of 21 DISEASE STATES INCREASE ANTICOAGULANT EFFICACY Blood dyscrasias 2 (hemophilia, von Willebrand s disease, thrombocytopenia) DECREASE ANTICOAGULANT EFFICACY Alcoholism (chronic) 4 Diarrhea 1 Edema 2 Elevated temperature 3 Hyperlipemia 1 Hepatic disease 2,4 Hereditary resistance* 2 Hyperthyroidism 3 Hypothyroidism 3 Inadequate diet 1 (esp. vitamin K deficiency) Nephrotic syndrome 4 Jaundice 2 Small bowel disease 1 Steatorrhea 1 1. vitamin K levels 1. vitamin K levels 2. synthesis/function of clotting 2. synthesis/function of clotting factors and/or platelets factors and/or platelets 3. clotting factor turnover 3. clotting factor turnover 4. drug metabolism/elimination 4. drug metabolism/elimination * Hereditary resistance to warfarin has been shown to be due to defects in the coagulation cascade, the most common of which are: APC resistance (factor V Leiden), protein S deficiency, protein C deficiency, antithrombin III deficiency PHYTONADIONE (Vitamin K 1 ) pharmacodynamic antagonist (not due to disappearance of warfarin, but rather the reestablishment of normal clotting factor activity) takes 24 hours fresh-frozen plasma or factor IX concentrates are also effective

20 Page 20 of DROTRECOGIN ALFA (ACTIVATED PROTEIN C) DROTRECOGIN ALFA is approved for use in disseminated intravascular coagulation or DIC (fatal complication of septic shock). The use of activated protein C as a drug occurred as a result of a change in our understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation. Mechanism of Action recombinant version of protein C; activated by thrombin; requires Ca 2+, phospholipid and protein S as cofactors anti-coagulant actions: 1) destroys activated factors Va and VIIIa, resulting in thrombin formation 2) inhibits platelet activation 3) suppresses tissue factor expression fibrinolytic actions 1) attenuates thrombin-catalyzed activation of tpa inhibitors 2) decreases PAI-1 concentrations anti-inflammatory actions: 1) inhibits synthesis of tumor necrosis factor 2) inhibits neutrophil activation 3) blocks the release of cytokines from macrophages Therapeutic Indications decreases relative risk of death by 20% (up to 50% of patients die of sepsis within 6 months) Adverse Effects HEMORRHAGE: dose related, no increase in patients with renal or liver insufficiency

21 Page 21 of 21 ANTIPLATELET DRUGS ASA, ABCIXIMAB, CLOPIDOGREL, DIPYRIDAMOLE, EPTIFIBATIDE, TICLOPIDINE, TIROFIBAN Mechanisms of Action Inhibit platelet adhesion and aggregation by: 1. Inhibiting cyclooxygenase: e.g. ASA 2. Blocking glycoprotein IIb/IIIa receptor: e.g. ABCIXIMAB, EPTIFIBATIDE 3. Inhibiting the binding of fibrinogen to activated platelets: e.g. CLOPIDOGREL, TICLOPIDINE 4. Inhibiting cyclic nucleotide phosphodiesterase: e.g. DIPYRIDAMOLE